Bone formation (matrix synthesis) is the product of osteoblasts most immediately recruited and differentiated from stem cell populations located in the stromal compartment of bone marrow and in the periosteum. However, these are not the only stem cells with osteogenic developmental potential. Other stem cells which have the capacity form bone and cartilage are located in connective tissue in multiple parts of the body (e.g., muscle, spleen and thymus) and will undergo osteogenic differentiation upon exposure to an osteo-inductive agent. The physiological role of these inducible osteogenic precursor cells (IOPCs) is still a matter of speculation but one possibility is that they are part of a circulating pool of multipotential stem cells that may take up residence in marrow and contribute to osteogenesis in bone. It is now reasonably well established that the stem cell population located in the bone marrow stroma (determined osteogenic precursor cells; DOPCs) undergoes a marked age-related reduction in number and osteogenic potential, and it is likely that this reduction contributes to the decline in the level bone formation associated with Type II ("senile") osteoporosis. No such information on possible population change exists for IOPCs. In the present application, we propose to make this determination in young and old mice and guinea pigs using in vitro and in vivo methods established by the foreign collaborator, Prof. A. Friedenstein, for isolating, culturing and assessing the osteogenic potential of IOPCs derived from spleen and thymus. Specifically, we will determine (1) whether the spleen and thymus of old mice and guinea pigs contain fewer of the clonogenic precursor cells (CFU-f) and IOPCs than young animals, (2) whether explanted older animal IOPCs have reduced osteogenic potential and (3) whether there is a reduction in the capacity of older animals to respond to osteoinductive stimulation in situ. Should the latter be observed, it would provide indirect but important confirmation of lowered IOPC numbers and/or developmental potential in old animals.